Gene Therapy for Patients With Transfusion-Dependent β-Thalassemia

Overview

Thalassemia is a group of recessively inherited hemoglobin disorders characterized by reduced or no production of hemoglobin and chronic anemia of varying severity. Severe β-thalassemia is transfusion-dependent thalassemia (TDT) and requires life-long transfusion, iron overload is a common complication of TDT. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option currently available for TDT, but it carries significant acute and long-term risks. In this study, the autologous HSCT-based gene therapy (referred to as "gene therapy for thalassemia, " by using HGI-001) is based on the principle that the autologous haemopoietic stem cells (HSCs) collected from the patient him/herself are transduced outside human body, which will restore the function of RBCs, so as to achieve the effect of treating or even curing thalassemia. Currently data suggests that gene therapy for TDT patients has shown remarkable therapeutic effects, avoiding immune rejection, and is widely accepted by the medical community, positioning it as a highly promising treatment approach. To date, the efficacy and safety of HGI-001 have been evaluated through both in vitro and in vivo studies. In an early-phase clinical study of HGI-001 conducted in China, five patients achieved transfusion-independent post-treatment. Among them, four have maintained this state for over two years, with the longest duration reaching 3.5 years. The study noted no severe adverse events. The long-term safety and efficacy of HGI-001 continue to be under active surveillance.

This is a single-arm, open-label, single-dose, single site study in approximately 6 subjects ≥12 and ≤45 years of age with TDT. Subjects must have TDT with a transfusion history of at least 100mL/kg/year of packed red blood cells (pRBCs) or 8 transfusions of pRBCs per year in the past 2 years before enrollment. Stage 1: Screening to determine eligibility for treatment: Subjects with previously known β0/β0 or non-β0/β0 genotypes are eligible for screening. Stage 2: Autologous CD34+ cell collection, HGI-001 Injection manufacture and disposition: Each subject will undergo HSC mobilization with a granulocyte-colony stimulating factor (G-CSF) and plerixafor. Peripheral blood mononuclear cells (PBMCs) will be collected by apheresis. A total of 2 mobilization cycles may be performed if needed and each mobilization cycle may include up to 3 days for apheresis. Stage 3: Myeloablative conditioning and infusion of HGI-001 Injection (Day 0) : the subject will undergo myeloablative conditioning with busulfan. After completion of the 4-day course of busulfan, there must be a minimum of 48 hours of washout period before administration of HGI-001 Injection. On study Day 0, after thawing, the HGI-001 Injection will be administered via intravenous (IV) infusion at a dose of \>4.0 × 106 CD34+ cells/kg. Stage 4: Follow-up, through engraftment and up to 12 months after HGI-001 Infusion: Subjects will be followed up daily in the transplant unit for adverse events (AEs), and laboratory parameters will be followed up to monitor bone marrow engraftment. The subject will be discharged from the transplant unit once the subject is considered clinically stable. The goal during the follow-up period is to maintain hemoglobin (Hb) ≥9 g/dL. Transfusions should be avoided for patients with Hb ≥9 g/dL, unless the transfusion need is medically justified (e.g., as a pre-requirement for surgery).